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Liver cancer in a dish: modelling hepatocellular carcinoma using patient-derived tumor organoids

Nuciforo, Sandro. Liver cancer in a dish: modelling hepatocellular carcinoma using patient-derived tumor organoids. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12969

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Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most frequent cause of cancer-related mortality worldwide. HCC predominantly arises in cirrhotic livers as a consequence of underlying chronic diseases including viral hepatitis, alcoholic liver disease and non-alcoholic steatohepatitis. Treatment options for advanced HCC are limited. Sorafenib (Nexavar®) has been the only approved drug for the management of advanced HCC for the past ten years. Recently, additional multikinase inhibitors entered the clinic, however, without significantly improving overall survival as compared to sorafenib. Major advancements are expected to be achieved with the introduction of immune checkpoint inhibitors such as nivolumab (Opdivo®), but biomarkers to identify patients who may benefit from the treatment are currently missing. Moreover, several additional drugs have failed to meet clinical end points in large phase III trials, indicating a need for new drug discovery for HCC.
A major obstacle for the development of new therapies is the lack of suitable preclinical animal models or cell culture systems that allow a faithful translation of basic research findings into the clinical setting. This thesis describes the generation of organoids derived from needle biopsies of HCCs. The use of tumor biopsies instead of surgically resected HCC specimens is important because it allows to generate organoids from all tumor stages, whereas surgical resection of HCCs is limited to a minority of patients with small, early stage tumors. These tumors are typically not treated with systemic therapies, and material derived from them might have limited value for developing new treatments for advanced HCCs.
Because of the very limited amount of tissue that can be obtained with a needle biopsy, generation of HCC organoids was technically challenging. A key to our success was the immediate sample processing. The biobank of tumor organoids described in this study encompasses different etiologies and, most importantly, all clinical tumor stages. Our study design also allowed to compare the organoids with the originating tumor biopsies. We found that HCC organoids preserve the morphological characteristics and tumor marker expression of their originating tumors. Moreover, a comprehensive analysis of the genetic landscape in both, primary tumors and corresponding organoids, revealed a high concordance of the molecular alterations and the genetic heterogeneity, confirming that the organoids are a genuine representation of the originating tumors. In addition, tumor organoids can be successfully transplanted and propagated in immunodeficient mice to generate xenografts. Finally, in a proof of concept study, we show that tumor organoids can be used to test sensitivities to clinically-relevant drugs and provide a promising novel tool for developing tailored therapies.
Advisors:Heim, Markus H. and Affolter, Markus
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Hepatologie > Hepatologie (Heim)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Hepatologie > Hepatologie (Heim)
UniBasel Contributors:Heim, Markus H. and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12969
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (109 Seiten)
Language:English
Identification Number:
Last Modified:05 Apr 2019 04:30
Deposited On:04 Apr 2019 10:13

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